Peptide compounds of (L) amino acids and ring molecules, and therapeutical applications thereof

ABSTRACT

Compounds of general formula A--B--C in which: A is a monovalent radical of a L-ring molecule; B is a bivalent radical of a L-α-aminoacid; and C is a monovalent radical of a L-aromatic molecule. The compounds show an anti-hypertensive, analgesic, immuno-modulating and antiinflammatory activity, they are resistant to enzyme hydrolysis and they can be used for the preparation of drugs for oral administration.

This application is a continuation of application Ser. No. 08/311,449,filed on Sep. 26, 1994, now U.S. Pat. No. 5,504,071, which is acontinuation of application Ser. No. 07/867,231, filed Jun. 2, 1992, nowabandoned, the entire contents of which are hereby incorporated byreference.

TECHNICAL FIELD

The present invention has as its object compounds having multiplepharmacological activity, and having present in their molecule asequence of three radicals, of which the central one is an α-aminoacidic radical. These compounds, which show a good level of resistanceto enzymatic hydrolysis, can be used in the preparation of drugs, inparticular for oral use, having anti-hypertensive, analgesic,immunomodulating and antiinflammatory activities.

1. Background Art

As is known, in Italian patents No. 1 172 391 and 1 186 733, and in thepublished Italian patent application No. 48430A89, molecules of peptidicnature are known, having anti-hypertensive, analgesic andimmunomodulating activity, characterized by the sequence of threeradicals of specific α-amino acids.

Said compounds have been shown to work well in the preparation of drugshaving the above characteristics.

However, their use has been limited to administration by injection, dueto the low resistance shown by these compounds to enzymatic hydrolysis.

2. Disclosure of the Invention

It has now been surprisingly found that the use of compounds accordingto the present invention makes it possible to overcome theabove-mentioned limitation, while at the same time offering otheradvantages which will be clearly seen from the following. Object of thepresent invention are compounds of general formula

    A--B--C

in which

A is a monovalent radical of a (L)-ring molecule selected from the groupcomprising: ##STR1## in which X can be CH₂, S or CHOH

n can be 0, 1, 2

R¹ can be H or CH₃

R can be H, CH₃, or a generic nitrogen blocking group as used in thesynthesis of peptides, such as CBZ, BOC, Fmoc and acetyl

Y can be CH₂ or CO

Z can be NH, NCH₃, O or S;

B is the bivalent radical of a neutral (L)-α-amino acid, selected fromthe group comprising glycine, leucine, alanine or valine; and

C is the monovalent radical of a (L)-aromatic amino acid, selected fromthe group comprising tryptophan, phenylalanine, phenylglycine, andsalts, esters and amides thereof, or one of the compounds listed below,and salts, esters and amides thereof, ##STR2## in which R¹ has themeaning previously indicated, and

R² can be H, OH, OCH₃ or CH₃,

with the proviso that when A is ##STR3## in which R has the meaningpreviously indicated, with the exclusion of CH₃,

then C cannot be either a residue of tryptophan, or of phenylalanine.

The present invention also extends to drugs with anti-hypertensive,analgesic, immuno-modulating and antiinflammatory activity,characterized by the fact that they contain at least one of thecompounds represented by the above general formula.

These drugs can be taken orally.

The present invention also extends to the use of compounds of thegeneral formula indicated above for the preparation of drugs, forexample for oral use, for the treatment of states of hypertension, forpain therapy, for the modulation of immune responses and for thetreatment of inflammatory states.

The drugs according to the present invention can naturally containnon-toxic, pharmaceutically inert, support materials. Among the suitablenon-toxic, pharmaceutically inert support materials can be includedsolid, semi-solid or liquid diluents, various fillers and additives, forexample binding, moistening, reticulating and adsorbtion agents, agentsfor delaying solution and accellerating absorption.

Examples of the possible pharmaceutical preparations can includetablets, sugar-coated pills, capsules, pills, granulates, suppositories,solutions, suspensions and emulsions, pastes, ointments, gels, cremes,lotions, powders and sprays.

Tablets, sugar-coated pills, capsules, pills and granulates can beprovided with the usual coatings and coverings, if necessary containingopacifiers, and they can be compounded in such a way as to release theactive agents only or preferably in a certain part of the intestine,with delayed action if necessary.

Said formulations can also contain dyes, preservatives and additives toimprove their smell and taste, for example oil of mint and eucalyptusoil and sweeteners, for example saccharin.

The pharmaceutical preparations mentioned can contain, as activeprinciples, other active pharmaceutical agents as well as the compoundsaccording to the present invention.

MODES FOR CARRYING OUT THE INVENTION

Up to now, a description of a general nature has been given of thecompounds object of the present invention. With the help of thefollowing examples a more detailed description is now given, with theaim of giving a better understanding of their objects, characteristicsand functional advantages.

In the following examples will first of all be given the data necessaryfor synthesis of the compounds according to the present invention. Therewill then be given data regarding their pharmacological activity, usingmethods widely known to be valid. In particular, for the pressure tests,spontaneously hyper-tensive rats were used (SHR from the company CharlesRiver), operated in such a way as to enable pressure to be read evenwhen the animals were awake and free to move. In order to evaluate theanalgesic activity, the Hot Plate and Writhing Tests were used. For theanti-inflammatory effect the test of carraginine edema was used.Finally, for immuno-modulating activity the evaluation of thestimulation of growth of human lymphocytes in culture was resorted to,after the addition of specific antigens. The results obtained for eachsynthesized compound are given at the end of each example.

For the components used in the examples, the following abbreviationshave been adopted:

(S)-CytOEt=Ethyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole-3-carboxylate

(1)-Me-(S)-CytOMe=Methyl-(1)-Methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole-3-carboxylate

(9)-Me-(S)-CytOMe=Methyl-(9)-Methyl-(S) -1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole-3-carboxylate

(5)-Me-(S)-CytOMe=Methyl-(5)-Methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!indole-3-carboxylate

5-OH-(S)-CytOMe=Methyl-(5)-hydroxy-(S)-1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole-3-carboxylate

TrpH=Tryptamine

CytH=Tryptoline (or: 1,2,3,4-tetrahydro-9H-pyrido 3,4-b!indole)

CypH=1,2,3,4-tetrahydro isoquinoline

(L)-OmtOMe=Methyl-4-methoxy-(L)-phenylalaninate

(L)-PhgOMe=Methyl-(L)-phenylglycinate

(L)-Pme=(S)-(-)-2-amino-1-methoxy-3-phenylpropane

2-Fur=2-furoic acid (or: furan-2-carboxylic acid)

2-Tiof=2-thiophenic acid (or: thiophene-2-carboxylic acid)

2-Pyrrolyl=pyrrole-2-carboxylic acid

1-Me-2-Pyrrolyl=1-methyl-pyrrole-2-carboxylic acid

2-Indolyl=indole-2-carboxylic acid

1-Me-2-indolyl=1-methyl-indole-2-carboxylic acid

N-Me-(L)-Pro=N-methyl-(L)-Proline

(L)-CypOMe=methyl-1,2,3,4-tetrahydro isoquinoline-3-carboxylate

(1)-Me-(L) -CypOMe=Methyl-(1)-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

(6)-MeO-(L)-CypOMe=Methyl-(6)-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Cpe=1,2,3,4-tetrahydro isoquinoline-3-methoxy methyl

(L)-Mep=(2)-methyl-(L)-Proline

∇³,4 -(L)-Pro=3,4 dihydro-(L)-Proline

(S)-Dhi=(S)-(-)-indoline-2-carboxylic acid

(L)-Pip=(L)-pipecholinic-2-carboxylic acid

(L)-Tia=(L)-(-)-thiazolidine-(4)-carboxylic acid

(S)-Aza=(S)-(-)-azetidinic-2-carboxylic acid

(S)-Tfc=(-)-tetrahydro furane-2-carboxylic acid.

EXAMPLE 1

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-(S)-CytOEt(compound 1)

A suspension of 1.830 g (5.71 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in100 ml of anhydrous tetrahydrofuran (THF) was brought under argonatmosphere to a temperature of approximately -20° C. On stabilization ofthe temperature, the following were added under stirring in quicksuccession: 0.820 ml (6.27 mmoles) of isobutylchloroformate (IBCF) and0.690 ml (6.28 mmoles) of 4-methylmorpholine (NMM), leaving the systemunder stirring for approximately 2 minutes. Then 0.850 g (6.29 mmoles)of anhydrous 1-hydroxybenzotriazole (HoBt) were added. The mixture wasleft under stirring for approximately 20 minutes, keeping thetemperature under control at approximately -15° C. A solution was thenadded, pre-cooled to -15° C. for 30 minutes, of 1.570 g (5.59 mmoles) of(S)-CytOEt.HCl (the free acid was prepared according to Brossi's methodA. Brossi, A. Forcella, S. Teitel: J.M.C. (1973), 16(4), 418! and thecorresponding ethyl ester was prepared according to Chan's method M. A.Brook, T. H. Chan: Synthesis, (1983) (3), 201!) and 0.620 ml (5.62mmoles) of NMM in 30 ml of anhydrous N,N-dimethylformamide (DMF).Leaving the temperature of the system free to rise to room temperature,after approximately one hour, 0.690 ml (6.28 mmoles) of NMM were againadded, maintaining stirring and static argon for a further 12 hours. Thewhite precipitate was then filtered away and washed with a littleanhydrous THF. The latter was put back into the reaction solution of ayellowish colour which, concentrated under vacuum to approximately onequarter of its original volume, was diluted four times with methylenechloride and was extracted in succession using 5% NaHCO₃ (4×30 ml);saturated aqueous NaCl (2×30 ml); 4% KHSO₄ (4×30 ml) and finallysaturated aqueous NaCl (3×30 ml), discarding the aqueous phases. Theorganic phase extracted was left in a cool chamber under argon and onanhydrous Na₂ SO₄ for 12 hours. The desiccant was then filtered away andthe solution concentrated to a small volume under vacuum. The residualyellowish oil was taken up with 30 ml of a methanol/anhydrous ethylether mixture (5:1), obtaining a limpid, yellowish solution which, afterelimination of the ethyl ether, was dripped slowly into an excess ofcold water. The large amount of white precipitate thus obtained, after acouple of hours in a cold chamber, is filtered, washed using 20 ml of awater/methanol solution (10:1) and dried under vacuum on P₂ O₅ for 24hours. 2.0 g (65.45%) of an analytically pure whiteish solid wererecovered.

This compound shows a good anti-hypertensive effect. At a dose of 4mg/Kg i.p., the pressure values were reduced by 15-20%, and the effectwas maintained for a number of hours.

At the same dose, a slight pain killing effect was also noted under theHot Plate test.

From an immunological point of view, the compound increases the responseof lymphocytes stimulated by phytohemoagglutinine (PHA).

The following compounds were prepared in a similar manner:

Z-(L)-Pro-(L)-Leu-(S)-CytOMe

Z-(L)-Pro-(L)-Leu-(1)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Leu-(9)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Ala-(1)-Me-(S)-CytoMe

Z-(L)-Pro-(L)-Ala-(5)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Ala-(9)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Ala-(1,5)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Ala-(5)-OH-(S)-CytOMe

Z-(L)-Pro-Gly-(S)-CytOMe

Z-(L)-Pro-Gly-(l)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Val-(l)-Me-(S)-CytOMe

Z-(L)-Pro-(L)-Val-(S)-CytOMe

EXAMPLE 2

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-TrpH(compound 2)

A suspension of 1.500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in60 ml of dry methylene chloride (CH₂ Cl₂) was brought under argonatmosphere to a temperature of approximately -20° C. On stabilization ofthe temperature, the following were added under stirring in quicksuccession: 0.620 ml (4.74 mmoles) of isobutylchloroformate (IBCF) and0.580 ml (4.77 mmoles) of N-methylpiperidine (NMP), leaving the systemunder stirring for approximately 2 minutes. A solution precooled to -15°C. for 30 minutes of 0.880 g (4.47 mmoles) of TrpH.HCl and 0.550 ml(4.52 mmoles) of NMP in 15 ml of anhydrous N,N-dimethylformamide (DMF)was then added to the white suspension. Under stirring, the temperatureof the system was allowed to rise to room temperature. Afterapproximately 3.5 hours of reaction, the white precipitate was filteredaway and washed with a little CH₂ Cl₂. The latter was put back into thereaction solution of a yellowish colour, which was extracted insuccession using 5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml);4% KHSO₄ (3×30 ml) and finally saturated aqueous NaCl (3×30 ml),discarding the aqueous phases. The organic phase extracted was left in acool chamber under argon and on anhydrous Na₂ SO₄ for 24 hours. Thedesiccant was then filtered away and the solution concentrated to asmall volume under vacuum. The residual yellowish liquid was drippedunder stirring into 150 ml of petroleum ether (30/50), obtaining arubbery grey precipitation. The solution was decanted and the residualmass was taken up with a minimum of CH₂ Cl₂ and further purified byflash-chromatography in a normal phase (SiO₂, eluant CH₂ Cl₂/n-Hexane/n-PrOH 10:1.5:0.5). Having collected and joined together thefractions of interest, most of the eluant was eliminated under vacuumand precipitation with an excess of n-Hexane takes place. There was alarge amount of whiteish precipitate, slightly rubbery, which wasfiltered after a couple of hours and dried on P₂ O₅ under vacuum for 24hours. 1.300 g (62.8%) of an analytically pure whiteish solid wererecovered.

On pressure, this compound has an activity comparable to that ofcompound 1. The immune response was also increased, but to a lesserextent than in the previous compound.

EXAMPLE 3

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-CytH(compound 3)

A suspension of 1.500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in70 ml of dry methylene chloride (CH₂ Cl₂) was brought in an argonatmosphere to a temperature of approximately -20° C. On stabilization ofthe temperature, the following were added under stirring in quicksuccession: 0.620 ml (4.74 mmoles) of isobutylchloroformate (IBCF) and0.580 ml (4.77 mmoles) of N-methylpiperidine (NMP), leaving the systemunder stirring for approximately 2 minutes. Adding 0.650 g (4.81 mmoles)of anhydrous 1-hydroxybenzotriazole (HOBT), the temperature was kept,under stirring, at approximately -15° C. for a further 20 minutes, thenadding 0.780 g (4.53 mmoles) of CytH (Aldrich). Leaving the temperatureof the system free to rise to room temperature, after approximately onehour another 0.580 ml (4.77 mmoles) of NMP were added. The mixture wasleft under stirring, static argon, out of the light, for 12 hours. Thesolid white precipitate was filtered away and washed with a littlemethylene chloride, which was put back into the reaction solution of ayellowish colour. This was extracted in succession using 5% NaHCO₃ (3×30ml); saturated aqueous NaCl (2×30 ml); 4% KHSC₄ (3×30 ml) and finallysaturated aqueous NaCl (3×30 ml), discarding the aqueous phases. Theorganic phase extracted was left in a cool chamber under argon and onanhydrous Na₂ SO₄ for 24 hours. The desiccant was then filtered away andthe solution concentrated to a small volume under vacuum, obtaining aresidual yellowish oil which was taken up with anhydrous ethyl ether.The ether solution thus obtained was brought back to a dry state undervacuum and the residual yellow oil, taken up with the smallest possiblevolume of acetate mixture of ethyl/n-hexane (2:1) was purified byflash-chromatography in a normal phase (SiO₂, eluant ethylacetate/n-hexane: 2/1.5). Having joined and concentrated the fractionsof interest under vacuum a dense pale yellow oil was left which, whentaken up with a minimum quantity of methanol, was precipitated in anexcess of water, obtaining an abundant flocculent whiteish precipitate.After two hours rest in a cold chamber the off-white precipitate wasfiltered and dried under vacuum on P₂ O₅ for 24 hours. 1.520 g (70.7%)of an analytically pure, slightly rubbery off-white solid wererecovered.

The compound Z-(L)-Pro-(L)-Ala-CypH was prepared in a similar manner.

The compound shows a bland anti-hypertensive effect, at a dose of 8mg/Kg/i.p.

EXAMPLE 4

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-(L)-OmtOMe(compound 4)

A suspension of 1.600 g (5.00 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in70 ml of dry methylene chloride (CH₂ Cl₂) was brought, under stirringand in an argon atmosphere, to the temperature of the ice and salt bath.The following were then added in succession: 0.850 g (5.03 mmoles) ofcommercial 1-hydroxybenzotriazole (HOBt) and 0.960 g (5.01 mmoles) ofN-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping thetemperature under control, the mixture was left under stirring for 10minutes and then the following were added in succession: 1.210 g (4.92mmoles) of OmtOMe.HCl, prepared (according to Chan's method) from4-methoxy-(L)-phenylalanine (Aldrich) and 0.550 ml (4.99 mmoles) of4-methylmorpholine (NMM), maintaining the temperature for a further 2hours. The mixture was then left under stirring and static argon for 12hours with the temperature free to rise to room temperature. The solidwhite precipitate was filtered away and washed with a little CH₂ Cl₂.The latter was put back into the filtered reaction solution, which wasextracted in succession using 5% NaHCO₃ (3×30 ml); saturated aqueousNaCl (2×30 ml); 4% KHSO₄ (3×30 ml) and saturated aqueous NaCl (3×30 ml),discarding the aqueous phases. The organic phase extracted was left in acool chamber under argon and on anhydrous Na₂ SO₄ for 12 hours. Thedesiccant was then filtered away, the solution concentrated to a smallvolume and dripped under stirring into approximately 180 ml of drypetroleum ether (30/50), obtaining an abundant milk-white precipitation,which after a few hours at rest in a cold chamber was filtered and leftfor 12 hours under vacuum on P₂ O₅. 2.020 g (80.2%) of an analyticallypure milk-white solid were recovered.

The compound shows a bland anti-hypertensive effect, at a dose of 8mg/Kg/i.v.. The immune response was also slightly increased.

EXAMPLE 5

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-(L)-PhgOMe(compound 5)

A suspension of 1.500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in60 ml of dry methylene chloride (CH₂ Cl₂) was brought, under stirringand in an argon atmosphere, to the temperature of the ice and salt bath.The following were then added in succession: 0.800 g (4.73 mmoles) ofcommercial 1-hydroxybenzotriazole (HOBt) and 0.900 g (4.69 mmoles) ofN-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping thetemperature under control, the mixture was left under stirring for 10minutes and then the following were added in succession: 0.940 g (4.66mmoles) of (L)-PhgOMe.HCl (Bachem) and 0.520 ml (4.72 mmoles) of4-methylmorpholine (NMM), maintaining the temperature for a further 2hours. The mixture was then left under stirring and static argon for 12hours with the temperature free to rise to room temperature. The solidwhite precipitate was filtered away and washed with a little CH₂ Cl₂.The latter was put back into the filtered reaction solution, which wasextracted in succession using 5% NaHCO₃ (3×30 ml); saturated aqueousNaCl (2×30 ml); 4% KHSO₄ (3×30 ml) and finally saturated aqueous NaCl(2×30 ml), discarding the aqueous phases. The organic phase extractedwas left in a cold chamber under argon and on anhydrous Na₂ SO₄ for 12hours. The desiccant was then filtered away, the solution concentratedto a small volume and the dense residual liquid was ground withanhydrous ethyl ether a number of times, decanting each time anddiscarding the ether phase. The residual solid was left for 24 hoursunder vacuum on P₂ O₅. 1.630 g (74.8%) of an analytically pure powderywhite solid were recovered.

The compound shows a bland anti-hypertensive effect, at a dose of 8mg/Kg/i.p.. It also has a moderate analgesic effect when tested usingthe Hot Plate test.

The following compounds were prepared in a similar manner:

Z-(L)-Pro-(L)-Leu-(L)-PhgOMe

Z-(L)-Pro-(L)-Val-(L)-PhgOMe

Z-(L)-Pro-Gly-(L)-PhgOMe

EXAMPLE 6

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala-(L)-Pme(compound 6)

A suspension of 1.550 g (4.84 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in60 ml of dry methylene chloride (CH₂ Cl₂) was brought, under stirringand under argon atmosphere, to the temperature of the ice and salt bath.The following were then added in succession: 0.820 g (4.85 mmoles) ofcommercial 1-hydroxybenzotriazole (HOBt) and 0.930 g (4.85 mmoles) ofN-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping thetemperature under control, the mixture was left under stirring for 10minutes and then the following were added in succession: 0.970 g (4.81mmoles) of (L)-Pme.HCl (Fluka) and 0.530 ml (4.81 mmoles) of4-methylmorpholine (NMM), maintaining, the temperature for a further 2hours. The mixture was then left under stirring and static argon for 12hours with the temperature free to rise to room temperature. The solidwhite precipitate was filtered away and washed with a little CH₂ Cl₂.The latter was put back into the filtered reaction solution, which wasextracted in succession using 5% NaHCO₃ (3×30 ml); saturated aqueousNaCl (2×30 ml); 4% KHSO₄ (3×30 ml) and finally saturated aqueous NaCl(2×30 ml), discarding the aqueous phases. The organic phase extractedwas left in a cold chamber under argon and on anhydrous Na₂ SO₄ for 12hours. The desiccant was then filtered away, the solution concentratedto a small volume and dripped into 150 ml of dry petroleum ether(30/50), obtaining an abundant, slightly rubbery milk-white precipitate.This was left at rest in a cold chamber for a few hours and then thesolid white precipitate was filtered under vacuum and ground withanhydrous ethyl ether, discarding the ether phase. The residual whitesolid was left for 24 hours under vacuum on P₂ O₅, 1.870 g (80.1%) of ananalytically pure white solid were recovered.

The compound has a good anti-hypertensive activity at a dose of 2 mg/Kgi.v.. After one hour the pressure was reduced by approximately 25%. Thecompound furthermore has a good analgesic activity, expressed in a 70%reduction of contorsions during the Writhing test, and extension of time(25%) in the Hot Plate test. The anti-inflammatory effect appears to berather weak, while the increase in immunological activity was moreconsistent. The following compounds have been prepared in a similarmanner:

Z-(L)-Pro-(L)-Leu-(L)-Pme

Z-(L)-Pro-(L)-Val-(L)-Pme

Z-(L)-Pro-Gly-(L)-Pme

EXAMPLE 7

Synthesis and pharmacological activity ofZ-(L)-Pro-(L)-Ala-(1)-Me-(L)-TrpOMe (compound 7)

A suspension of 2.100 g (6.55 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in80 ml of dry methylene chloride (CH₂ Cl₂) was brought, under argonatmosphere, to a temperature of approximately -20° C. On stabilizationof the temperature, the following were added in rapid succession: 0.850ml (6.50 mmoles) of isobutylchloroformate (IBCF) and 0.790 ml (6.50mmoles) of N-methylpiperidine (NMP), leaving the system under stirringfor approximately 2 minutes. A solution pre-cooled to -15° C. for 30minutes of 1.700 g (6.32 mmoles) of TrpOMe.HCl, prepared (according toChan's method) from 1-Me-(DL)-TrpOH (Aldrich) and 0.770 ml (6.33 mmoles)of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) was then addedto the white suspension. Under stirring, the temperature of the systemwas allowed to rise to room temperature. After approximately 4 hours ofreaction, the white precipitate was filtered away and washed with alittle CH₂ Cl₂. The latter was put back into the reaction solution of ayellowish colour, which was extracted in succession using 5% NaHCO₃(4×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO₄ (4×30 ml) andfinally saturated aqueous NaCl (3×30 ml), discarding the aqueous phases.The organic phase extracted was left in a cold chamber under argon andon anhydrous Na₂ SO₄ for 24 hours. The desiccant was then filtered awayand the solution concentrated to a small volume under vacuum. Theresidual yellowish liquid was dripped under stirring into 150 ml ofn-hexane, obtaining a large amount of white precipitate, which wasfiltered after resting for several hours in a cold chamber, leaving thewhite solid under vacuum on P₂ O₅ for 12 hours. 2.700 g (85.0%) of awhite solid were recovered, which on analysis was shown to beZ-(L)-Pro-(L)-Ala-(1)-Me-(DL)-TrpOMe. The two diastereoisomers wereseparated by flash-chromatography in an inverse phase (resin C₁₈, eluantH₂ O/CH₃ CN 60:40), collecting and uniting the fractions of interest. Onelimination under vacuum of most of the organic phase, an abundant whiteflocculent precipitation was obtained which, after several hours at restin a cold chamber, was filtered under vacuum. The filtered solid wasdried for 24 hours on P₂ O₅ under vacuum. 1.0 g (31.5%) of ananalytically pure white solid corresponding toZ-(L)-Pro-(L)-Ala-(1)-Me-(L)-TrpOME were recovered.

The compound has a good anti-hypertensive effect, as at a dose of 2mg/Kg i.v. a reduction of 10% in basic pressure was obtained inspontaneously hypertensive animals. The compoundZ-(L)-Pro-(L)-Ala-(5)-Me-(L)-TrpOMe has been obtained in a similarmanner.

EXAMPLE 8

Synthesis and pharmacological activity of 2-Fur-(L)-Leu-(L)-TrpOMe(compound 8)

A suspension of 1.0 g (2.72 mmoles) of (L)-Leu-(L)-TrpOMe.HCl(Novabiochem) in 60 ml of dry methylene chloride (CH₂ Cl₂) was brought,under argon atmosphere, to the temperature of the ice and salt bath.0.490 ml (6.07 mmoles) of dried pyridine were then added and, afterapproximately 10 minutes, a solution of 0.290 ml (2.96 mmoles) of2-FurCl (Fluka) in 20 ml of dried CH₂ Cl₂, freshly distilled, was addeddropwise, controlling the temperature of the bath. On completing theadditions, the reaction mixture was left under stirring, in an argonatmosphere and out of the light for approximately 4 hours. The mixturewas then beaten in succession with 5% NaHCO₃ (3×30 ml), saturatedaqueous NaCl (2×30 ml), 4% KHSO₄ (3×30 ml) and finally saturated aqueousNaCl (3×30 ml), discarding the aqueous phases. The organic phaseextracted was left in a cold chamber under argon and anhydrous Na₂ SO₄for 12 hours. The desiccant was then filtered away and the organicsolution, concentrated to a small volume under vacuum, was addeddropwise under stirring to approximately 200 ml of dry petroleum ether(30/50). The milk-white precipitate, after several hours at rest in acold chamber, was filtered under vacuum and washed with a small amountof CH₂ Cl₂ /petroleum ether mixture (1:10), discarding the organicsolution. It was then left for 24 hours on P₂ O₅ under vacuum. 0.750 g(65.0%) of an analytically pure off-white solid were recovered.

The compound shows a slight anti-hypertensive effect, at a dose of 4mg/Kg i.v.. On human lymphocytes, the immune response was stronglystimulated even with small doses of peptide. The compound also shows aslight antiinflammatory effect.

The following compounds have been obtained in a similar manner:

2-Fur-(L)-Ala-(L)-TrpOMe

2-Fur-(L)-Val-(L)-TrpOMe

2-Fur-(L)-Ala-(S)-CytOMe

2-Fur-Gly-(L)-TrpOMe

2-Tiof-(L)-Leu-(L)-TrpOMe

EXAMPLE 9

Synthesis and pharmacological activity of 2-Pyrrolyl-(L)-Leu-(L)-TrpOMe(compound 9)

A suspension of 0.800 g (7.20 mmoles) of 2-pyrrolylcarboxylic acid(Aldrich) in 60 ml of dry methylene chloride (CH₂ Cl₂) was brought,under argon, to the temperature of the ice and salt bath. The followingwere added successively under stirring: 1.380 g (7.20 mmoles) ofN-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC) and 1.170 g (7.21mmoles) of commercial 1-hydroxybenzotriazole (HOBt). Maintaining thetemperature of the bath, after 10 minutes a further 2.650 g (7.20mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.800 ml (7.26mmoles) of N-methylmorpholine were added, leaving the reaction mixtureunder agitation, in an argon atmosphere and out of the light for 12hours. The white precipitate was then filtered away and washed with alittle CH₂ Cl₂. The latter was put back into the reaction solution of abrownish-yellow colour, which was extracted in succession using 5%NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO₄ (3×30 ml)and finally saturated aqueous NaCl (3×30 ml), discarding the aqueousphase. The organic phase extracted was left under argon and out of thelight for 12 hours on anhydrous Na₂ SO₄. The desiccant was then filteredaway, the solution concentrated to a small volume under vacuum and theresidual yellow oil, taken up with the smallest possible amount of achloroform/acetone mixture (3:1), was purified usingflash-chromatography in a normal phase (SiO₂, eluant CHCl₃ /acetone:5.5/1). The chromatographic fractions, joined together and concentratedto a small volume, were added dropwise under stirring to 300 ml ofpetroleum ether (30/50), obtaining an abundant milk-white precipitate.After several hours at rest in a cold chamber, the off-white solid isfiltered and left for 24 hours under vacuum on KOH in drops, out of thelight. 1.450 g (47.4%) of an analytically pure dirty white solid wererecovered.

The compound shows a slight effect on pressure, and gives a blandreduction of inflammatory responses. The following compounds have beenprepared in a similar manner:

1-Me-2-Pyrrolyl-(L)-Leu-(L)-TrpOMe

1-Me-2-Indolyl-(L)-Leu-(L)-TrpOMe

2-Indolyl-(L)-Leu-(L)-TrpOMe

EXAMPLE 10

Synthesis and pharmacological activity ofN-Me-(L)-Pro-(L)-Leu-(L)-TrpOMe.HCl (compound 10)

A suspension of 1.0 g (7.74 mmoles) of N-Me-(L)-Pro,OH (Sigma) in 60 mlof dry methylene chloride (CH₂ Cl₂) was brought, in an argon atmosphere,to the temperature of an ice and salt bath. The following were thenadded in succession: 1.250 g (7.74 mmoles) of commercial1-hydroxybenzotriazole (HOBt) and 1.600 g (7.75 mmoles) ofN,N'-dicyclohexylcarbodiimmide (DCC), leaving the system under stirringand maintaining control of the temperature for a further 30 minutes. Tothe reaction mixture was then added with 2.800 g (7.61 mmoles) of(L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.840 ml (7.62 mmoles) of4-methylmorpholine (NMM), leaving the system under stirring for 12 hourswith the temperature free to rise to room temperature. The fine whiteprecipitate was then filtered away and washed with a little CH₂ Cl₂. Thelatter was put back into the filtered reaction solution, which wasconcentrated under vacuum to approximately half its original volume,filtering away the new white precipitate. It was then extracted insuccession using 5% NaHCO₃ (3×30 ml) and saturated aqueous NaCl (2×30ml), discarding the aqueous phases. The organic phase was then extractedwith acetate buffer at pH 4 (3×30 ml), discarding the organic phase. Theaqueous phase was brought to pH 6 and extracted using CH₂ Cl₂ (3×30 ml).The organic phase, extracted with saturated aqueous NaCl (2×30 ml), wasleft in a cold chamber, under argon atmosphere and anhydrous Na₂ SO₄ for24 hours. The desiccant was then filtered away, the organic solutionconcentrated to a small volume and the residual yellowish liquid addeddropwise under energetic stirring to an excess of dry petroleum ether(30/50), obtaining an abundant white precipitate. After several hours ina cold chamber the white solid was filtered and, taken up at the limitof solubility with anhydrous dioxane, was precipitated again in anexcess of a solution of 1.0M of gaseous HCl in anhydrous ethyl ether.After leaving the suspension to rest in a cold chamber for approximately1 hour, the excess of acid was eliminated under a flow of dry nitrogen,then adding a large excess of anhydrous ethyl ether. The abundant finemilk-white precipitation, filtered under vacuum and washed in a littleanhydrous ethyl ether, was left for 24 hours under vacuum on P₂ O₅.2.550 g (70.0%) of an analytically pure semi-crystalline white solidwere recovered.

The compound has an excellent anti-hypertensive effect, and at a dose of2 mg/Kg i.v. pressure was reduced by 15-20%. The immune response wasslightly increased, and the substance also shows a low analgesic effect.The following compounds have been prepared in a similar manner:

N-Me-(L)-Pro-(L)-Ala-(L)-TrpOMe.HCl

N-Me-(L)-Pro-(L)-Val-(L)-TrpOMe.HCl

N-Me-(L)-Pro-(L)-Ala-(S)-CytOMe.HCl

N-Me-(L)-Pro-Gly-(L)-TrpOMe.HCl

EXAMPLE 11

Synthesis and pharmacological activity of Z-(L)-Pro-(L)-Ala(L)-CypOMe(compound 11)

A suspension of 1.600 g (5.0 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in80 ml of dry methylene chloride (CH₂ Cl₂) was brought in an argonatmosphere to a temperature of approximately -20° C. On stabilization ofthe temperature, the following were added in quick succession: 0.670 ml(5.13 mmoles) of isobutylchloroformate (IBCF) and 0.570 ml (5.17 mmoles)of 4-methylmorpholine (NMM), leaving the system under stirring forapproximately 2 minutes.

Adding 0.700 g (5.18 mmoles) of anhydrous 1-hydroxybenzotriazole (HOBT),the temperature was kept at approximately -15° C for a further 20minutes. A solution, pre-cooled to approximately -15° C. for 30 minutes,of 1.100 g (4.83 mmoles) of (L)-CypOMe.HCl, prepared (according toChan's method) from (L)-1,2,3,4-tetrahydro-3-isoquinolinic acidhydrochlorate (Bachem) and 0.540 ml (4.90 mmoles) of NMM in 20 ml ofanhydrous N,N-dimethylformamide (DMF) was then added to the reactionmixture. Leaving the temperature of the bath free to rise to roomtemperature, after approximately one hour a further 0.570 ml (5.17mmoles) of NMM were added, continuing stirring and static argon for afurther 12 hours. The white precipitate was then filtered away andwashed with a little CH₂ Cl₂. The latter was put back into the reactionsolution, which was extracted in succession using 5% NaHCO₃ (3×30 ml);saturated aqueous NaCl (2×30 ml); 4% KHSO₄ (3×30 ml) and finallysaturated aqueous NaCl (3×30 ml), discarding the aqueous phases. Theorganic phase extracted was left in a cold chamber under argon and onanhydrous Na₂ SO₄ for 24 hours. The desiccant was then filtered away,the organic solution concentrated to a small volume under vacuum, andthe residual thick oil was taken up with ethyl acetate at the limit ofsolubility and added dropwise to an excess of a mixture (5:1) ofn-hexane/ethyl ether. An initial oily white precipitate was obtainedwhich, after 24 hours in a cold chamber, thickens. After decanting anddiscarding the precipitation solution the residual solid was taken upwith the smallest possible amount of absolute ethyl alcohol and theresulting solution was added dropwise to a large excess of water. Anabundant white precipitation was obtained which, after 12 hours in acold chamber, was filtered and left under vacuum on P₂ O₅ for 24 hours.1.260 g (52.8%) of an analytically pure, slightly rubbery, dirty whitesolid were recovered.

The compound shows a slight anti-hypertensive effect, together with amoderate anti-inflammatory effect.

The following compounds were prepared in a similar manner:

Z-(L)-Pro-(L)-Leu-(L)-CypOMe

Z-(L)-Pro-(L)-Val-(L)-CypOMe

Z-(L)-Pro-Gly-(L)-CypOMe

Z-(L)-Pro-(L)-Ala-(l)-Me-(L)-CypOMe

Z-(L)-Pro-(L)-Ala-(6)-MeO-(L)-CypOMe

Z-(L)-Pro-(L)-Ala-(1)-Me-(6)-MeO-(L)-CypOMe

Z-(L)-Pro-(L)-Leu-(1)-Me-(L)-CypOMe

Z-(L)-Pro-(L)-Ala-(L)-Cpe

EXAMPLE 12

Synthesis and pharmacological activity of Boc-(L)-Mep-(L)-Leu-(L)-TrpOMe(compound 12)

A suspension of 1.150 g (5.02 mmoles) ofN-tert.butyloxycarbonyl-(2)-methyl-(L)-proline (abbreviationBoc-(L)-MepOH, prepared according to the method of Thaisrivongs S.Thaisrivongs, D. T. Pais, J. A. Lawson, S. R. Turner, D. W. Harris:J.M.C. 30, 536 (1987)! using 2-methyl-(L)-proline, prepared according tothe method of Seebach D. Seebach, M. Boes, R. Naif, W. B. Schwerzer;J.A.C.S. 105, 5390 (1983)!) in 60 ml of dry methylene chloride (CH₂ Cl₂)was brought under argon atmosphere to a temperature of approximately-20° C. On stabilization of the temperature, the following were added inquick succession: 0.670 ml (5.13 mmoles) of isobutylchloroformate (IBCF)and 0.630 ml (5.18 mmoles) of 4-methylpiperidine (NMP), leaving thesystem under stirring for approximately 2 minutes. A solution,pre-cooled to approximately -15° C. for 30 minutes of 1.780 g (4.84mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.600 ml (4.93mmoles) of NMP in 25 ml of anhydrous N,N-dimethylformamide (DMF) wasthen added to the reaction mixture, leaving, under stirring and staticargon, the temperature of the bath free to rise to room temperature.After approximately 5 hours of reaction, the white precipitate was thenfiltered away and washed with a little CH₂ Cl₂. The latter was put backinto the pale yellow coloured organic solution, which was extracted insuccession using 5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml);4% KHSO₄ (3×30 ml) and finally saturated aqueous NaCl (3×30 ml),discarding the aqueous phases. The organic phase extracted, of a paleyellow colour, was left in a cold chamber under argon and on anhydrousNa₂ SO₄ for 12 hours. The desiccant was then filtered away and theorganic solution, concentrated to a small volume under vacuum, waspurified using flash-chromatography in a normal phase (SiO₂, eluant CH₂Cl₂ /n-hexane: 4/1). The chromatographic fractions of interest, joinedtogether and concentrated to a small volume, were precipitated by alarge excess of n-hexane, obtaining an abundant white precipitate which,after several hours at rest in a cold chamber, was filtered, discardingthe organic solution. The residual solid was left for 24 hours undervacuum on KOH in drops. 1.450 g (55.2%) of an analytically purepseudo-crystalline white solid were recovered.

The compound shows a bland anti-hypertensive effect, and also showsreduction of the inflammatory response (edema from carrageenin).

EXAMPLE 13

Synthesis and pharmacological activity of Boc-∇³,4-(L)-Pro-(L)-Leu-(L)-TrpOMe (compound 13)

A suspension of 1.000 g (4.67 mmoles) ofN-tert.butyloxycarbonyl-3.4-dehydro-(L)-proline (abbreviation Boc-∇³,4-(L)-Pro, (Bachem)) in 60 ml of dry methylene chloride (CH₂ Cl₂) wasbrought under argon atmosphere to a temperature of approximately -20° C.On stabilization of the temperature, the following were added in quicksuccession: 0.630 ml (4.82 mmoles) of isobutylchloroformate (IBCF) and0.590 ml (4.85 mmoles) of 4-methylpiperidine (NMP), leaving the systemunder stirring for approximately 2 minutes. A solution, precooled toapproximately -15° C. for 30 minutes, of 1.670 g (4.54 mmoles) of(L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.560 ml (4.61 mmoles) of NMPin 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added to thereaction mixture, leaving, under stirring and static argon, thetemperature of the bath free to rise to room temperature. Afterapproximately 4.5 hours of reaction, the white precipitate was filteredaway and washed with a little CH₂ Cl₂. The latter was put back into thepale yellow coloured organic solution, which was extracted in successionusing 5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO₄(3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding theaqueous phases. The organic phase extracted, of a pale yellow colour,was left in a cold chamber under argon and on anhydrous Na₂ SO₄ for 12hours. The desiccant was then filtered away and the organic solution,concentrated to a small volume, was purified using flash-chromatographyin a normal phase (SiO₂, eluant CH₂ Cl₂ /methanol 2%). Thechromatographic fractions of interest, joined together and concentratedto a small volume, were precipitated by a large excess of n-hexane,obtaining an abundant white precipitate which, after several hours atrest in a cold chamber, was filtered, discarding the organic solution.The residual solid was left for 24 hours under vacuum on KOH in drops.1.440 g (60.2%) of an analytically pure pseudo-crystalline white solidwere recovered.

The compound was slightly anti-hypertensive, and slightly increases theimmune response. The following compounds have been prepared in a similarmanner:

Boc-∇³,4 -(L)-Pro-(L)-Ala-(L)-TrpOMe

Boc-∇³,4 -(L)-Pro-(L)-Val-(L)-TrpOMe

Boc-∇³,4 -(L)-Pro-(L)-Ala-(S)-CytOMe

Boc-∇³⁴ -(L)-Pro-Gly-(L)-TrpOMe

EXAMPLE 14

Synthesis and Pharmacological activity of Z-(S)-Dhi-(L)-Leu-(L)-TrpOMe(compound 14)

A suspension of 1.500 g (5.04 mmoles) ofN-benzyloxycarbonyl-(S)-(-)-indoline-2-carboxylic acid (abbreviationZ-(S)-DhioH, prepared from (S)-(-)-indoline-2-carboxylic acid (Aldrich)according to the method of Wunsch E. Wunsch, W. Graf, O. Keller, W,Keller, G. Wersin: Synthesis, (11), 958 (1986)!) in 80 ml of drymethylene chloride (CH₂ Cl₂) was brought under argon atmosphere to atemperature of approximately -20° C. On stabilization of thetemperature, the following were added in quick succession: 0.680 ml(5.20 mmoles) of isobutylchloroformate (IBCF) and 0.580 ml (5.26 mmoles)of 4-methylmorpholine (NMM), leaving the system under stirring forapproximately 2 minutes. A solution, precooled to approximately -15° C.for 30 minutes, of 1.840 g (5.00 mmoles) of (L)-Leu-(L)-TrpOMe.HCl(Novabiochem) and 0.560 ml (5.08 mmoles) of NMM in 25 ml of anhydrousN,N-dimethylformamide (DMF) was then added, leaving, under stirring andstatic argon, the temperature of the bath free to rise to roomtemperature. After approximately 5 hours of reaction, the whiteprecipitate was then filtered away and washed with a little CH₂ Cl₂. Thelatter was put back into the pale yellow coloured organic solution,which was extracted in succession using 5% NaHCO₃ (3×30 ml); saturatedaqueous NaCl (2×30 ml); 4% KHSO₄ (3×30 ml) and finally saturated aqueousNaCl (3×30 ml), discarding the aqueous phases. The organic phaseextracted, of a pale yellow colour, was left in a cold chamber underargon and on anhydrous Na₂ SO₄ for 12 hours. The desiccant was thenfiltered away and the organic solution, concentrated to a small volume,was added dropwise under stirring to 200 ml of dry petroleum ether(30/50), obtaining an abundant white precipitate which, after severalhours at rest in a cold chamber, was filtered, discarding the organicsolution. The residual solid was left for 24 hours under vacuum on P₂O₅. 2.440 g (79.9%) of an analytically pure white solid were recovered.

The compound induces a bland reduction of pressure, and has a moderateanalgesic effect. The following compounds have been prepared in asimilar manner:

Z-(S)-Dhi-(L)-Ala-(L)-TrpOMe

Z-(S)-Dhi-(L)-Val-(L)-TrpOMe

Z-(S)-Dhi-(L)-Ala-(S)-CytOMe

Z-(S)-Dhi-Gly-(L)-TRpOMe

EXAMPLE 15

Synthesis and pharmacological activity of Z-(L)-Pip-(L)-Leu-(L)-TrPOMe(compound 15)

A suspension of 1.300 g (4.94 mmoles) ofN-benzyloxycarbonyl-(L)-pipecoline-2-carboxylic acid (abbreviationZ-(L)-PipOH, prepared from (L)-pipecholine-2-carboxylic acid (Aldrich)according to the method of Wunsch) in 60 ml of dry methylene chloride(CH₂ Cl₂) was brought under argon atmosphere to a temperature ofapproximately -20° C. On stabilization of the temperature, the followingwere added in quick succession: 0.670 ml (5.13 mmoles) ofisobutylchloroformate (IBCF) and 0.630 ml (5.18 mmoles) of4-methylpiperidine (NMP;), leaving the system under stirring forapproximately 2 minutes. A solution, pre-cooled to approximately -15° Cfor 30 minutes, of 1.730 g (4.70 mmoles) of (L)-Leu-(L)-TrpOMe.HCl(Novabiochem) and 0.580 ml (4.77 mmoles) of NMP in 25 ml of anhydrousN,N-dimethylformamide (DMF) was then added, leaving, under stirring andstatic argon, the temperature free to rise to room temperature. Afterapproximately 3,5 hours of reaction, the white precipitate was filteredaway and washed with a little CH₂ Cl₂. The latter was put back into thepale yellow coloured organic solution, which was extracted in successionusing 5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO₄(3×30 ml) and finally saturated aqueous NaCl (3×30 ml) , discarding theaqueous phases. The organic phase extracted, of a pale yellow colour,was left in a cold chamber under argon and on anhydrous Na₂ SO₄ for 12hours. The desiccant was then filtered away and the organic solution,concentrated to a small volume, was added dropwise under stirring to 200ml of dry petroleum ether (30/50), obtaining an abundant milk-whiteprecipitate which, after several hours at rest in a cold chanber, wasfiltered and left for 24 hours under vacuum on P₂ O₅. 2.300 g (84.8%) ofan analytically pure white solid were recovered.

The compound shows a good anti-hypertensive effect, with a decrease ofpressure valued of up to 30% after 2 mg/Kg i.v. The reduction of theinflammatory response also appears to be consistent, while a slightincrease in immune response can be seen.

The following compounds have been prepared in a similar manner:

Z-(L)-Pip-(L)-Ala-(L)-TrpOMe

Z-(L)-Pip-(L)-Val-(L)-TrpOMe

Z-(L)-Pip-(L)-Ala-(S)-CytOMe

Z-(L)-Pip-Gly-(L)-TrpOMe

Boc-(L)-Tia-(L)-Leu-(L)-TrpOMe

EXAMPLE 16

Synthesis and pharmacological activity of Z-(L)-Hyp-(L)-Leu-(L)-TrpOMe(compound 16)

A suspension of 1.600 g (4.98 mmoles) ofN-benzyloxycarbonyl-O-tButyl-trans-hydroxy-(L)-proline (abbreviationZ-O-tBu-(L)-HypOH, (Bachem)) in 70 ml of dry tetrohydrofuran (THF) wasbrought under argon atmosphere to a temperature of approximately -20° C.On stabilization of the temperature, the following were added in quicksuccession: 0.670 ml (5.13 mmoles) of isobutylchloroformate (IBCF) and0.570 ml (5.17 mmoles) of 4-methylmorpholine (NMM), leaving the systemunder stirring for approximately 2 minutes. A solution, precooled toapproximately -15° C. for 30 minutes, of 1.800 g (4.89 mmoles) of(L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.540 ml (4.90 mmoles) of NMPin 25 ml of anhydrous N,N-dimethylformamide (DMF) was then added,leaving, under stirring and static argon, the temperature free to riseto room temperature. After approximately 5 hours of reaction, the whiteprecipitate was filtered away and washed with a little THF. The latterwas put back into the pale yellow coloured organic solution, which,after having been concentrated under vacuum and taken up with threetimes the volume of methyl chloride, was extracted in succession using5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHS₄ (3×30 ml)and finally saturated aqueous NaCl (3×30 ml), discarding the aqueousphases. The organic phase extracted, of a pale yellow colour, was leftin a cold chamber under argon and on anhydrous Na₂ SO₄ for 12 hours. Thedesiccant was then filtered away and the organic solution, concentratedto a small volume, was ground with an excess of anhydrous ethyl ether.The solid precipitate, after filtering, was taken up in the smallestpossible quantity of ethyl acetate (AcOEt) and purified on an aluminacolumn (eluant AcOEt/n-hexane: 5/1). The chromatographic fractions ofinterest, after being recovered and concentrated to a small volume, wereprecipitated with dry petroleum ether (30/50), obtaining a heavy whitesolid which, after several hours, was filtered and taken up withanhydrous dioxane. The solution thus obtained was treated under stirringand at the temperature of the ice bath with a solution of 4N gaseous HClin anhydrous dioxane, in the presence of N-methylindole. Afterapproximately 30 minutes the excess of gaseous HCl was eliminated undera flow of N₂, the residue was concentrated under vacuum and precipitatedwith a large excess of a mixture (1:1) of anhydrous ethyl ether/dryn-hexane, obtaining an abundant milk-white precipitation which, afterseveral hours at rest, was filtered and left overnight under vacuum onP₂ O₅. 1.500 g (53.0%) of an analytically pure heavy white solid wererecovered.

The compound shows a bland anti-hypertensive action, joined to a modestanalgesic effect.

EXAMPLE 17

Synthesis and pharmacological activity of Z-(S)-Aze-(L)-Leu-(L)-TrpOMe(compound 17)

A suspension of 1.200 g (5.10 mmoles) ofN-benzyloxycarbonyl-(S)-(-)-2-azetidine-carboxylic acid (abbreviationZ-(S)-AzeOH, prepared from (S)-(-)-2-azetidinecarboxylic acid (Aldrich)according to the method of Wunsch) in 60 ml of dry methylene chloride(CH₂ Cl₂) was brought in an argon atmosphere to a temperature ofapproximately -20° C. On stabilization of the temperature, the followingwere added in quick succession: 0.690 ml (5.27 mmoles) ofisobutylchloroformate (IBCF) and 0.650 ml (5.34 mmoles) of4-methylpiperidine (NMP), leaving the system under stirring forapproximately 2 minutes. A solution, pre-cooled to approximately -15° C.for 30 minutes, of 1.850 g (5.03 mmoles) of (L)-Leu-(L)-TrpOMe.HCl(Novabiochem) and 0.620 ml (5.10 mmoles) of NMP in 25 ml of anhydrousN,N-dimethylformamide (DMF) was then added, leaving, under stirring andstatic argon, the temperature free to rise to room temperature. Afterapproximately 3.5 hours of reaction, the white precipitate was filteredaway and washed with a little CH₂ Cl₂. The latter was put back into thepale yellow coloured organic solution, which was extracted in successionusing 5% NaHCO₃ (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO₄(3×30 ml) and finally saturated aqueous NaCl (3×30 ml), discarding theaqueous phases. The organic phase extracted, of a pale yellow colour,was left in a cold chamber under argon and on anhydrous Na₂ SO₄ for 12hours. The desiccant was then filtered away and the organic solution,concentrated to a small volume, leaves a dense residual oil which, whentaken up with a minimum amount of CH₂ Cl₂, was purified usingflash-chromatography in a normal phase (SiO₂, eluant CH₂ Cl₂ /n-hexane:2/1). The chromatographic fractions of interest were concentrated to asmall volume and ground with anhydrous ethyl ether. The whiteish solidthus obtained was filteres and left for 24 hours under vacuum on P₂ O₅.2.040 g (75.0%) of an analytically pure rubbery white solid wererecovered.

The compound shows a slight anti-hypertensive effect nd blandanti-inflammatory activity. The following compounds have been preparedin a similar manner:

Z-(S)-Aze-(L)-Ala-(L)-TrpOMe

Z-(S)-Aze-(L)-Val-(L)-TrpOMe

Z-(S)-Aze-(L)-Ala-(S)-CytOMe

Z-(S)-Aze-Gly-(L)-TrpOMe

EXAMPLE 18

Synthesis and pharmacological activity of (S)-Tfc-(L)-Leu-(L)-TrpOMe(compound 18)

A suspension of 0.500 g (5.21 mmoles) of (-)tetrahydrofuran-2-carboxylicacid (Aldrich) in 50 ml of dry methylene chloride (CH₂ Cl₂) was broughtunder argon atmosphere to the temperature of an ice and salt bath.

The following were then added in succession under stirring: 0.880 g(5.21 mmoles) of commercial hydroxybenzotriazole (HOBt) and 1.070 g(5.19 mmoles) of N.N'-dicyclohexylcarbodiimide (DCC). After 10 minutes,a further 1.900 g (5.16 mmoles) of (L)-Leu-(L)-TrpOMe.HCl (Novabiochem)and 0.570 ml (5.17 mmoles) of 4-methylmorpholine (NMM) were added,maintaining the temperature of the bath for a further 2 hours. Themixture was then left, under static argon, out of the light, and withthe temperature free to rise to room temperature, under stirring for 12hours. The white precipitate was then filtered away and washed with alittle CH₂ Cl₂. The latter was put back into the pale yellow colouredfiltered reaction solution, which was dried out under vacuum. Theyellowish solid thus obtained was ground with an excess of water and theaqueous solution, after extraction with ethyl acetate, was treated understirring for 12 hours with ion-exchange resin Bio-Rad AG-501 X8 (D). Onfiltering away the resin, the aqueous solution was freeze-dried and thewhite solid thus recovered was ground with anhydrous ethyl ether,discarding the organic phase after decanting. The analytically purewhite solid thus obtained (1.660 g, 74.8%) was separated into its twodiastereoisomers by flash-chromatography in an inverted phase (resinC₁₈, eluant CH₃ CN 30/H₂ O 70 v/v), recovering the fractions of interestwhich, when joined together, concentrated and freeze-dried in theirturn, give 0.580 g (34.9% with respect to the pure diastereoisomericpair) of an analytically pure white solid.

The compound shows a bland anti-hypertensive effect, and stimulates theimmune response in a moderate manner.

EXAMPLE 19

Synthesis and pharmacological activity of Z-(L)-Pyr-(L)-Leu-(L)-TrpOMe(compound 19)

A suspension of 1.300 g (4.94 mmoles) ofN-benzyloxycarbonyl-(L)-pyroglutammic acid (abbreviation Z-(L)-PyrOH(Sigma) in 60 ml of dry methylene chloride (CH₂ Cl₂) was brought underargon atmosphere to a temperature of approximately -20° C. Onstabilization of the temperature, the following were added insuccession: 0.670 ml (5.13 mmoles) of isobutylchloroformate (IBCF) and0.630 ml (5.18 mmoles) of 4-methylpiperidine (NMP), leaving the systemunder stirring for approximately 2 minutes. A solution, pre-cooled toapproximately -15° C. for 30 minutes, of 1.810 g (4.92 mmoles) of(L)-Leu-(L)-TrpOMe.HCl (Novabiochem) and 0.600 ml (4.94 mmoles) of NMPin 20 ml of anhydrous N,N-dimethylformamide (DMF) was then added,leaving the mixture under stirring and static argon for 12 hours withthe temperature free to rise to room temperature. After approximately4.0 hours of reaction, the white solid was filtered away and washed witha little CH₂ Cl₂. The latter was put back into the reaction solution,which was extracted in succession using 5% NaHCO₃ (3×20 ml); saturatedaqueous NaCl (1×20 ml); 4% KHSO₄ (3×20 ml) and finally saturated aqueousNaCl (2×20 ml), discarding the aqueous phases. The organic solutionextracted was left in a cold chamber under argon and on anhydrous Na₂SO₄ for 12 hours. The desiccant was then filtered away and the solutionconcentrated to a small volume under vacuum. The dense residual oil wasground twice with anhydrous ethyl ether, obtaining a solidification ofthe oil itself. The solid thus obtained was taken up with 40 ml of dryCH₂ Cl₂ and the solution was added dropwise under stirring to 200 ml ofanhydrous ethyl ether, obtaining a milk-white precipitate which, afterseveral hours at rest in a cold chanber, was filtered and left for 24hours under vacuum on P₂ O₅. 1.850 g (65.2%) of an analytically pure,slightly rubbery white solid were recovered.

The compound shows a slight anti-hypertensive effect, joined to a fairanti-inflammatory activity. The following compounds have been preparedin a similar manner:

Z-(L)-Pyr-(L)-Ala-(L)-TrpOMe

Z-(L)-Pyr-(L)-Val-(L)-TrpOMe

Z-(L)-Pyr-Gly-(L)-TrpOMe

EXAMPLE 20

Synthesis and pharmacological activity of Z-(L)-Pyr-(L)-Leu-(S)-CytOMe(compound 20)

A suspension of 2.870 g (5.00 mmoles) of the 2,4,5 trichlorophenol esterof Z-(L)-Pyr-(L)-LeuOH acid (ester prepared according to Morley's methodJ. S. Morley, J.C.S., 2410 (1967)! from the Z-(L)-Pyr-(L)-LeuOH freeacid, prepared according to the method of Klieger E. Klieger, H. Gibian,Liebigs Ann. Chem. 649, 183 (1961)!) in 60 ml of anhydroustetrahydrofuran (THF) was brought under stirring and in an argonatmosphere to the temperature of an ice and salt bath. On stabilizationof the temperature, a pre-cooled solution of 1.270 g (5.51 mmoles) ofmethyl-(S)-1,2,3,4-tetrahydro-9H-pyrido- 3,4-b!-indole-3-carboxylate(abbreviation (S)-CytOMe, prepared by partition between 5% NaHCO₃ andethyl acetate, with the organic phase left to dry, after partition, for12 hours on anhydrous Na₂ SO₄, from the corresponding hydrochloride,prepared as previously described for Z-(L)-Pro-(L)-Ala-(S)-CytOMe) in 40ml of AcOEt. The temperature of the bath was kept under control forapproximately one hour and then, leaving the temperature free to rise toroom temperature, the mixture was left under stirring for a further 24hours. The reaction mixture was then concentrated to a small volume andadded dropwise under stirring to approximately 200 ml of anhydrous ethylether (Et₂ O), obtaining an abundant white precipitation which, afterbeing left to rest for several hours in a cold chamber, was filteredunder vacuum, discarding the ethyl solution. The solid obtained, whitein colour, was ground twice more with anhydrous Et₂ O and then once with30 ml of 5% NaHCO₃, discarding each time the filtered solutions. Thesolid was then left under vacuum on P₂ O₅ for 24 hours. 2.580 g (85.0%)of an analytically pure powdery white solid were recovered.

The compound shows a bland anti-hypertensive activity, joined to a fairanti-inflammatory activity.

The following compounds have been prepared in a similar manner:

Z-(L)-Pyr-(L)-Ala-(S)-CytOMe

Z-(L)-Pyr-(L)-Val-(S)-CytOMe

Z-(L)-Pyr-(L)-Leu-(1)-Me-(S)-CytOMe

Z-(L)-Pyr-(L)-Ala-(l)-Me-(S)-CytOMe

Z-(L)-Pyr-(L)-Val-(1)-Me-(S)-CytoMe

Z-(L)-Pyr-(L)-Leu-(9)-Me-(S)-CytoMe

Z-(L)-Pyr-Gly-(S)-CytOMe

EXAMPLE 21

Synthesis and pharmacological activity of Z-(L)-Pyr-(L)-Leu-(S)-CyPOMe(compound 21)

A suspension of 2.500 g (4.36 mmoles) of the 2,4,5-trichlorophenol esterof Z-(L)-Pyr-(L)-LeuOH acid (ester prepared according to Morley's methodfrom the Z-(L)-Pyr-(L)-LeuOH free acid, prepared according to the methodof Klieger) in 60 ml of anhydrous tetrahydrofuran (THF) was broughtunder stirring and in an argon atmosphere to the temperature of an iceand salt bath. On stabilization of the temperature, a pre-cooledsolution in 30 ml of AcOEt of 0.920 g (4.81 mmoles) of (L)-CypOMe,prepared by partition between 5% NaHCO₃ and ethyl acetate, with theorganic phase left to dry, after partition, for 12 hours on anhydrousNa₂ SO₄, from the corresponding hydrochloride, prepared as previouslydescribed for Z-(L)-Pro-(L)-Ala-(L)-CypOMe). The temperature of the bathwas kept under control for approximately one hour and then, leaving thetemperature free to rise to room temperature, the mixture was left understirring for a further 24 hours. The reaction mixture was thenconcentrated to a small volume and the dense residual oil was groundthree times with 50 ml of anhydrous n-hexane, discarding the solutions.A rubbery, yellowish-white solid was recovered which, taken up in aminimum quantity of methyl chloride, was further purified byflash-chromatography in a normal phase (SiO₂, eluant CH₂ Cl₂). Havingrecovered, united and concentrated to a small volume the chromatographicfractions of interest, these were added dropwise to 100 ml of anhydrousn-hexane, obtaining a rubbery white solid which tends to solidify over aperiod of time. After 24 hours in a cold chamber the organic solutionwas decanted and the residual solid was left under vacuum on P₂ O₅ for12 hours. 1.780 g (74.3%) of an analytically pure, slightly rubberyheavy white solid were recovered.

The compound shows a slight anti-hypertensive activity, together with agood immuno-stimulating activity.

The following compounds have been prepared in a similar manner:

Z-(L)-Pyr-(L)-Ala-(S)-CypOMe

Z-(L)-Pyr-(L)-Val-(S)-CypOMe

Z-(L)-Pyr-(L)-Val-(l)-Me-(L)-CypOMe

Z-(L)-Pyr-(L)-Leu-(l)-Me-(L)-CypOMe

Z-(L)-Pyr-(L)-Ala-(1)-Me-(L)-CypOMe

Z-(L)-Pyr-(L)-Leu-(6)-MeO-(L)-CypOMe

Z-(L)-Pyr-Gly-(6)-MeO-(L)-CypOMe

Z-(L)-Pyr-Gly-(L)-CypOMe

Z-(L)-Pyr-(L)-Leu-(L)-Cpe

EXAMPLE 22

Synthesis and pharmacological activity of (L)-Pyr-Gly-(L)-PhgOMe(compound 22)

A suspension of 1.830 g (5.00 mmoles) of the 2,4,5 trichlorophenol esterof (L)-Pyr-GlyOH acid (ester prepared according to Morley's method fromthe (L)-Pyr-GlyOH free acid Novabiochem!) in 60 ml of dry methylchloride (CH₂ Cl₂) was brought under stirring and in an argon atmosphereto the temperature of an ice and salt bath. On stabilization of thetemperature, a pre-cooled solution of 0.910 mg (5.51 mmoles) of(L)-PghOMe (prepared by partition between 5% NaHCO₃ and CH₂ Cl₂₁ withthe organic phase left to dry, after partition, for 12 hours onanhydrous Na₂ SO₄, from the corresponding hydrochloride, (L)-PhgOMe.HClBachem!) in 40 ml of CH₂ Cl₂. The temperature of the bath was kept undercontrol for approximately one hour and then, leaving the temperaturefree to rise to room temperature, the mixture was left under stirringfor a further 24 hours. The reaction mixture was then concentrated to asmall volume and the dense residual oil was ground three times with 50ml of anhydrous ethyl ether, discarding the ether solutions. The powderywhite solid thus obtained was taken up with distilled water, filteringaway the insoluble part, and freeze-dried. 1.170 g (70.1%) of ahygroscopic and analytically pure white solid were recovered.

The compound shows an excellent anti-hypertensive activity, with areduction of 20% in the pressure value at 4 mg/Kg i.p. Theanti-inflammatory effect also appears very good, with a 70% reduction ofedema. The compound appears to increase the immune response.

The following compounds have been prepared in a similar manner:

(L)-Pyr-(L)-Ala-(L)-PhgOMe

(L)-Pyr-(L)-Val-(L)-PhgOMe

(L)-Pyr-(L)-Leu-(L)-PhgOMe

EXAMPLE 23

Synthesis and pharmacological activity of (L)-Pyr-Gly-(L)-Pme (compound23)

A suspension of 1.830 g (5.00 mmoles) of the 2,4,5 trichlorophenol esterof (L)-Pyr-GlyOH acid (ester prepared according to Morley's method fromthe (L)-Pyr-GlyOH free acid Novabiochem!) in 60 ml of dry methylchloride (CH₂ Cl₂) was brought under stirring and in an argon atmosphereto the temperature of an ice and salt bath. On stabilization of thetemperature, a pre-cooled solution of 0.910 mg (5.51 mmoles) of (L)-Pme(prepared by partition between 5% NaHCO₃ and CH₂ Cl₂, with the organicphase left to dry, after partition, for 12 hours on anhydrous Na₂ SO₄,from the corresponding hydrochloride, (L)-Pme.HCl Fluka!) in 40 ml ofCH₂ Cl₂. The temperature of the bath was kept under control forapproximately one hour and then, leaving the temperature free to rise toroom temperature, the mixture was left under stirring for a further 24hours. The reaction mixture was then concentrated to a small volume andthe dense residual oil was ground three times with 50 ml of anhydrousethyl ether, discarding the ether solutions. The powdery white solidthus obtained was taken up with distilled water, filtering away theinsoluble part, and freeze-dried. 1.250 g (74.9%) of a hygroscopic andanalytically pure white solid were recovered.

The compound shows a good anti-hypertensive activity at 8 mg/Kg i.p. Thecompound also has an excellent analgesic effect (reduction of 80% in theWrithing test) and a good immuno-stimulating effect.

The following compounds have been prepared in a similar manner:

(L)-Pyr-(L)-Ala-(L)-Pme

(L)-Pyr-(L)-Leu-(L)-Pme

(L)-Pyr-(L)-Val-(L)-Pme

(L)-Pyr-(L)-Ala-(L)-Pho

(L)-Pyr-(L)-Leu-(L)-Pho

(L)-Pyr-(L)-Val-(L)-Pho

(L)-Pyr-Gly-(L)-Pho

EXAMPLE 24

Synthesis and pharmacological activity of (L)-Pyr-Gly-(L)-CypOMe(compound 24)

A suspension of 1.830 g (5.00 mmoles) of the 2,4,5 trichlorophenol esterof (L)-Pyr-GlyOH acid (ester prepared according to Morley's method fromthe (L)-Pyr-GlyOH free acid Novabiochem!) in 60 ml of dry methylchloride (CH₂ Cl₂) was brought under stirring and in an argon atmosphereto the temperature of an ice and salt bath. On stabilization of thetemperature, a pre-cooled solution of 1.050 mg (5.49 mmoles) of(L)-CypOMe (prepared by partition between 5% NaHCO₃ and CH₂ Cl₂, withthe organic phase left to dry, after partition, for 12 hours onanhydrous Na₂ SO₄, from the corresponding hydrochloride, prepared aspreviously described for Z-Pro-Ala-CypOMe) in 40 ml of CH₂ Cl₂. Thetemperature of the bath was kept under control for approximately onehour and then, leaving the temperature free to rise to room temperature,the mixture was left under stirring for a further 24 hours. The reactionmixture was then concentrated to a small volume and the dense residualoil was ground three times with 50 ml of anhydrous n-hexane, discardingthe ether solutions. The rubbery whitish solid thus obtained was takenup with a minimum quantity of CH₂ Cl₂ and purified usingflash-chromatography in a normal phase (SiO₂, eluant CH₂ Cl₂). Thechromatographic fractions of interest, after being recovered andconcentrated to a small volume, were ground with dry petroleum ether(30/50), obtaining a white, slightly rubbery solid, which was left undervacuum on P2O₅ for 24 hours. 1.240 g (68.9%) of an analytically purewhite solid were recovered.

The compound shows a bland anti-hypertensive action and a moderateanti-inflammatory action.

The following compounds have been prepared in a similar manner:

(L)-Pyr-Gly-(1)-Me-(L)-CypOMe

(L)-Pyr-Gly-(6)-MeO-(L)-CypOMe

(L)-Pyr-Gly-(L)-Cpe

(L)-Pyr-(L)-Ala-(L)-CypOMe

(L)-Pyr-(L)-Leu-(L)-CypOMe

(L)-Pyr-(L)-Val-(L)-CypOMe

(L)-Pyr-(L)-Leu-(1)-Me-(L)-CypOMe

(L)-Pyr-(L)-Ala-(l)-Me-(L)-CypOMe

(L)-Pyr-(L)-Val-(l)-Me-(L)-CypOMe

(L)-Pyr-(L)-Leu-(6)-MeO-(L)-CypOMe

(L)-Pyr-Gly-(L)-Cpe

(L)-Pyr-Gly-(L)-OmtOMe

(L)-Pyr-(L)-Leu-(L)-OmtOMe

(L)-Pyr-(L)-Ala-(L)-OmtOMe

(L)-Pyr-(L)-Val-(L)-OmtOMe

EXAMPLE 25

Synthesis and pharmacological activity of (L)-Pyr-(L)-Leu-(S)-CytOMe(compound 25)

A suspension of 2.100 g (4.98 mmoles) of the 2,4,5 trichlorophenol esterof (L)-Pyr-(L)-LeuOH acid (ester prepared according to Morley's methodfrom the (L)-Pyr-(L)-LeuOH free acid Novabiochem!) in 60 ml of drymethyl chloride (CH₂ Cl₂) was brought under stirring and in an argonatmosphere to the temperature of an ice and salt bath. On stabilizationof the temperature, a pre-cooled solution of 1.260 g (5.46 mmoles) of(S)-CytOMe, prepared as previously described forZ-(L)-Pyr-(L)-Leu-(S)-CytOMe, in 40 ml of CH₂ Cl₂. The temperature ofthe bath was kept under control for approximately one hour and then,leaving the temperature free to rise to room temperature, the mixturewas left under stirring for a further 12 hours. The reaction mixture,concentrated to a small volume, was then added dropwise to approximately200 ml of anhydrous ethyl ether (Et₂ O), obtaining an abundant whiteprecipitate which, after several hours at rest in a cold chamber, wasvacuum filtered, discarding the ether solution. The white solid thusobtained was ground once again with anhydrous Et₂ O and left undervacuum on P₂ O₅ for 24 hours. 1.880 g (79.8%) of an analytically purewhite solid were recovered.

The compound has a bland anti-hypertensive effect, joined to a weakanalgesic activity.

The following compounds have been prepared in a similar manner:

(L)-Pyr-(L)-Ala-(S)-CytOMe

(L)-Pyr-(L)-Val-(S)-CytOMe

(L)-Pyr-(L)-Leu-(1)-Me-(S)-CytOMe

(L)-Pyr-(L)-Ala-(1)-Me-(S)-CytOMe

(L)-Pyr-(L)-Leu-(9)-Me-(S)-CytOMe

(L)-Pyr-Gly-(l)-Me-(S)-CytoMe

(L)-Pyr-Gly-(S)-CytOMe

We claim:
 1. Compounds of general formula A--B--C in which A is amonovalent radical of a ring molecule selected from the group consistingof: ##STR4## in which X can be CH₂, S or CHOHn can be 0, 1, or 2 R¹ canbe H or CH₃, R can be H, CH₃, or a generic nitrogen blocking group asused in the synthesis of peptides selected from the group consisting ofCBZ, BOC, Fmoc and acetyl Y can be CH₂, or CO Z can be NH, NCH₃, O or S;B is a bivalent radical of an neutral (L)-α-amino acid, selected fromthe group consisting of glycine, leucine, alanine and valine; and C isthe monovalent radical of a (L)-aromatic amino acid selected from thegroup consisting of MeCytOMe, MeCytOH, CytOMe, CytOH, CypOMe, TrpOMe,PhgOMe, wherein CBZ is carbobenzoxy, MeCytOMe ismethyl-(1)-methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4b!-indole-3-carboxylate, or MeCytOMe ismethyl-(9)-methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, or MeCytOMe ismethyl-(5)-methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, MeCytOH is the free acid form of MeCytOMe,CytOMe is methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, CytOH is the free acid form of CytOMe,CyoOMe is (L)-1,2,3,4-tetrahydro-3-isoquinoline methyl ester, TrpOMe istryptophan methyl ester, PhgOMe is phenyl-glycine methyl ester andsalts, esters and amides thereof, wherein the compound of formulaA--B--C is notN-CBZ-Pro-Leu-CytOEt, N-CBZ-Pro-Ala-PhgOMe2-Fur-Leu-TrPOMe, 2-Tiof-Leu-TrpOMe, 2-Pyrrolyl-Leu-TrpOMe,N-Me-Pro-Ala-CytOMe, N-CBZ-Pip-Leu-TrpOME, Pyr-Leu-Cyt, or2-Fur-Leu-CytOMe,with the proviso that when A is ##STR5## in which R hasthe meaning previously indicated, with the exclusion of CH₃, then Ccannot be either a residue of trytophan, or of phenylalanine.
 2. Amethod for the treatment of hypertension which comprises administeringan effective amount of a compound according to claim 1 to a patient inneed thereof.
 3. A method for the treatment of pain which comprisesadministering an effective amount of a compound according to claim 1 toa patient in need thereof.
 4. A method for modulating the immuneresponse which comprises administering an effective amount of a compoundaccording to claim 1 to a patient in need thereof.
 5. A method for thetreatment of inflammatory states which comprises administering aneffective amount of a compound according to claim 1 to a patient in needthereof.
 6. A method according to any one of claims 2-5 which comprisesorally administering said compound.
 7. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and apharmacologically active compound of the following general formula:

    A--B--C

in which A is a monovalent radical of a ring molecule selected from thegroup consisting of: ##STR6## in which X can be CH₂, S or CHOH n can be0, 1, or 2 R¹ can be H or CH₃ R can be H, CH₃, or a generic nitrogenblocking group as used in the synthesis of peptides selected from thegroup consisting of CBZ, BOC, Fmoc and acetyl Y can be CH₂, or CO Z canbe NH, NCH₃, O or S; B is a bivalent radical of an neutral (L)-α-aminoacid, selected from the group consisting of glycine, leucine, alanineand valine; and C is the monovalent radical of a (L)-aromatic amino acidselected from the group consisting of MeCytOMe, MeCytOH, CytOMe, CytOH,CypOMe, TrpOMe, PhgOMe, wherein CBZ is carbobenzoxy, MeCytOMe ismethyl-(1)-methyl-(S)-1,2,3,4-tetrahydro-9H -pyrido3,4-b!-indole-3-carboxylate, or MeCytOMe ismethyl-(9)-methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, or MeCytOMe ismethyl-(S)-methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, MeCytOH is the free acid form of MeCytOMe,CytOMe is methyl-(S)-1,2,3,4-tetrahydro-9H-pyrido3,4-b!-indole-3-carboxylate, CytOH is the free acid form of CytOMe,CypOMe is (L)-1,2,3,4-tetrahydro-3-isoquinoline methyl ester, TrpOMe istryptophan methyl ester, PhgOMe is phenyl-glycine methyl ester andsalts, esters and amides thereof, wherein the compound of formula A-B-Cis notN-CBZ-Pro-Leu-CytOEt, N-CBZ-Pro-Ala-PhgOMe 2-Fur-Leu-TrpOMe,2-Tiof-Leu-TrpOMe, 2-Pyrrolyl-Leu-TrpOMe, N-Me-Pro-Ala-CytOMe,N-CBZ-Pip-Leu-TrpOMe, Pyr-Leu-Cyt, or 2-Fur-Leu-CytOMe,with the provisothat when A is ##STR7## in which R has the meaning previously indicated,with the exclusion of CH₃, then C cannot be either a residue oftrytophan, or of phenylalanine.
 8. A pharmaceutical compositionaccording to claim 7, wherein said pharmaceutically acceptable excipientis selected from the group consisting of diluents, fillers, binders,moistening agents, reticulating agents, adsorption agents, agents fordelaying solution and agents for accelerating absorption.
 9. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is selected from the group consistingof:2-Fur-(L)-Leu-(L)-CytOMe, 2-Fur-(L)-Leu-(L)-MeCytOH, and2-Fur-(L)-Leu-(L)-TrpOMe.
 10. A pharmaceutical composition according toclaim 7 wherein said pharmacologically active compound is selected fromthe group consisting of:N-Me-(L)-ProLeu-(S)-TrpOMe,N-Me-(L)-ProLeu-(S)-CytOMe, and N-Me-(L)-ProLeu-(S)-MeCytOH.
 11. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is selected from the group consistingof:(L)-Pyr-(L)-Leu-(S)-CypOMe, (L)-Pyr-(L)-Leu-(S)-CytOMe, and(L)-Pyr-(L)-Leu-(S)-MeCytOMe.
 12. A pharmaceutical composition accordingto claim 7 wherein said pharmacologically active compound is selectedfrom the group consisting of:Tfc-(L)-Leu-(S)-Me-CytOH, andTfc-(L)-Leu-(S)-CytOH.
 13. A pharmaceutical composition according toclaim 7 wherein said pharmacologically active compound is selected fromthe group consisting of:2-Tiof-(L)-Leu-(L)-MeCytOH, and2-Tiof-(L)-Leu-(L)-CytOMe.
 14. A pharmaceutical composition according toclaim 7 wherein said pharmacologically active compound is selected fromthe group consisting of:Z-(L)-Pro-(L)-Ala-(S)-CypOMe,Z-(L)-Pro-(L)-Ala-(S)-CytOH, Z-(L)-Pro-(L)-Ala-(S)-CytoMe, andZ-(L)-Pro-(L)-Ala-(S)-MeCytOMe.
 15. A pharmaceutical compositionaccording to claim 7 wherein said pharmacologically active compound isselected from the group consisting of:Z-(L)-Pro-(L)-Leu-(S)-CytOMe,Z-(L)-Pro-(L)-Leu-(S)-PhgOMe, and Z-(L)-Pro-(L)-Leu-(S)-MeCytOMe.
 16. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is selected from the group consistingof:Z-(L)-Pyr-(L)-Leu-(S)-CytOMe.
 17. A pharmaceutical compositionaccording to claim 7 wherein said pharmacologically active compound isselected from the group consistingof:Boc-(L)-(cis,trans)-(L)-Hyp-(L)-Leu-(S)-CytOH,Boc-(L)-Pro-(L)-Leu-(S)-CytOH, and (L)-Hyp-(L)-Leu-(S)-CytOH.
 18. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is selected from the group consistingof:2-Indolyl-(L)-Ala-(S)-CytOMe, N-Me-(L)-Pro-(L)-Ala-(S)-CytOMe,(L)-Pip-(L)-Ala-(S)-CytOMe, and (L)-Pyr-(L)-Ala-(S)-CytOMe.
 19. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is selected from the group consistingof:1-Me-2-Pyrrolyl-(L)-Leu-(L)-TrpOMe, and Z-(L)-Pip-(L)-Leu-(L)-TrpOMe.20. A pharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is(L)-Pyr-Gly-CytOMe.
 21. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound is2-Pyrrolyl-Gly-PhgOMe.
 22. Apharmaceutical composition according to claim 7 wherein saidpharmacologically active compound isZ-(L)-Pro-(L)-Val-CytOMe.